title: 2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one: a potent human NK1 receptor antagonist with multiple clearance pathways.
abstract: Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK1 receptor antagonist with a long duration of action and improved profile of CYP3A4 inhibition and induction compared to aprepitant. However, compound 2 is predicted, based on data in preclinical species, to have a human half-life longer than 40 h and likely to have drug-drug-interactions (DDI), as 2 is a victim of CYP3A4 inhibition caused by its exclusive clearance pathway via CYP3A4 oxidation in humans. We now report 2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one (3) as a next generation NK1 antagonist that possesses an additional clearance pathway through glucuronidation in addition to that via CYP3A4 oxidation. Compound 3 has a much lower propensity for drug-drug interactions and a reduced estimated human half-life consistent with once daily dosing. In preclinical species, compound 3 has demonstrated potency, brain penetration, and a safety profile similar to 2, as well as excellent pharmacokinetics.
authors.affiliation: Discovery Chemistry, ‡In Vitro Pharmacology, §Drug Metabolism, and ∥Laboratory Animal Resources, Merck Research Laboratories, Merck & Co. , Rahway, New Jersey 07065, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kassick
authors.forename: Jinlong
authors.initials: J
authors.lastname: Jiang
authors.forename: Jaime
authors.initials: J
authors.lastname: Bunda
authors.forename: David
authors.initials: D
authors.lastname: Wilson
authors.forename: Jianming
authors.initials: J
authors.lastname: Bao
authors.forename: Huagang
authors.initials: H
authors.lastname: Lu
authors.forename: Peter
authors.initials: P
authors.lastname: Lin
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ball
authors.forename: George A
authors.initials: GA
authors.lastname: Doss
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Kwei-Lan C
authors.initials: KL
authors.lastname: Tsao
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Gary
authors.initials: G
authors.lastname: Chicchi
authors.forename: Bindhu
authors.initials: B
authors.lastname: Karanam
authors.forename: Richard
authors.initials: R
authors.lastname: Tschirret-Guth
authors.forename: Koppara
authors.initials: K
authors.lastname: Samuel
authors.forename: Donald F
authors.initials: DF
authors.lastname: Hora
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kumar
authors.forename: Maria
authors.initials: M
authors.lastname: Madeira
authors.forename: Waisi
authors.initials: W
authors.lastname: Eng
authors.forename: Richard
authors.initials: R
authors.lastname: Hargreaves
authors.forename: Mona
authors.initials: M
authors.lastname: Purcell
authors.forename: Liza
authors.initials: L
authors.lastname: Gantert
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Cook
authors.forename: Robert J
authors.initials: RJ
authors.lastname: DeVita
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
mesh_terms: D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D054833:Isoindoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008657:Metabolic Clearance Rate; D064729:Neurokinin-1 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C586848:2-(5-(1-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl)-1,3-oxazol-4(5H)-one; D065692:Cytochrome P-450 CYP3A Inhibitors; D020719:Glucuronides; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D010080:Oxazoles; D010446:Peptide Fragments; C068032:GR 73632; D013373:Substance P; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human